Tropical Logistic Regression Model on Space of Phylogenetic Trees.

Classification of gene trees is an important task both in the analysis of multi-locus phylogenetic data, and assessment of the convergence of Markov Chain Monte Carlo (MCMC) analyses used in Bayesian phylogenetic tree reconstruction. The logistic regression model is one of the most popular classification models in statistical learning, thanks to its computational speed and interpretability. However, it is not appropriate to directly apply the standard logistic regression model to a set of phylogenetic trees, as the space of phylogenetic trees is non-Euclidean and thus contradicts the standard assumptions on covariates. It is well-known in tropical geometry and phylogenetics that the space of phylogenetic trees is a tropical linear space in terms of the max-plus algebra. Therefore, in this paper, we propose an analogue approach of the logistic regression model in the setting of tropical geometry. Our proposed method outperforms classical logistic regression in terms of Area under the ROC Curve in numerical examples, including with data generated by the multi-species coalescent model. Theoretical properties such as statistical consistency have been proved and generalization error rates have been derived. Finally, our classification algorithm is proposed as an MCMC convergence criterion for Mr Bayes. Unlike the convergence metric used by Mr Bayes which is only dependent on tree topologies, our method is sensitive to branch lengths and therefore provides a more robust metric for convergence. In a test case, it is illustrated that the tropical logistic regression can differentiate between two independently run MCMC chains, even when the standard metric cannot.

The COVID-19 Uninsured Program: Nearly 39 Million Vaccine Doses Were Funded, 2020-22.

The COVID-19 Uninsured Program, administered by the Health Resources and Services Administration (HRSA), reimbursed providers for administering COVID-19 vaccines to uninsured US adults from December 11, 2020, through April 5, 2022. Using HRSA claims data covering forty-two states, we estimated that the program funded about 38.9 million COVID-19 vaccine doses, accounting for 5.7 percent of total doses distributed and 10.9 percent of doses administered to adults ages 19-64.

A Systematic Review and Meta-Analysis of the Management of Gallstone Cholecystitis and Common Biliary Duct Stones to Reduce the Incidence of Complications in Elderly Patients.

As the age increases particularly above the age of 50 years, there is a significantly higher risk of developing gallstone-related complications especially cholecystitis and common bile duct stones with its associated consequences. Complications that arise after surgical operations for cholecystitis have been reported to have negative impacts on senior patients. These effects include a higher rate of complications, a longer hospital stay, higher expenditures, and decreased patient satisfaction. Therefore, finding the most effective treatment for cholecystitis in older patients is still a challenge. The aim of the study was carried out in order to identify many approaches that can be taken in the treatment of cholecystitis and stones in the common bile duct in older patients. A search was conducted through Medline (PubMed), EMBASE, ProQuest, and Cochrane using relevant Medical Subject Heading (MeSH) terms and keywords (elderly, age over 50, cholecystitis, bile duct stones, cholecystectomy, ERCP, surgical, conservative management, and open). The searches were limited to studies on elderly individuals over 50 who had cholecystectomy and endoscopic retrograde cholangiopancreatography between January 2000 and December 2022. The meta-analysis used the Mantel-Haenszel odds ratio (MHOR) and 95% confidence interval (CI). Aries Systems Corporation's Editorial Manager® (Aries Systems Corporation, North Andover, USA) and ProduXion Manager® (Aries Systems Corporation, North Andover, USA) facilitated the study. Out of 102 citations, 39 studies were selected for further study. After that, 18 studies were eliminated, leaving 21 for meta-analysis. The study found a protective risk of cholecystitis in cholecystectomy patients (MHOR = 0.16; 95%, CI = 0.10 to 0.25; p 0.001). Developing cholecystitis was substantially lower in early cholecystectomy patients (MHOR = 0.16; 95%, CI = 0.10 to 0.25; p 0.001). There was no significant difference in cholecystitis risk between open and laparoscopic surgery (MHOR = 0.65; 95%, CI = 0.41 to 1.04; p 0.07). Cholecystectomy performed at an earlier stage protects elderly patients from developing recurrent cholecystitis. In contrast to late cholecystitis, in which the patient would experience several attacks of cholecystitis, early cholecystectomy protects against the recurrence of the condition.

Assessment of the pathogen genomics landscape highlights disparities and challenges for effective AMR Surveillance and outbreak response in the East African community.

The East African Community (EAC) grapples with many challenges in tackling infectious disease threats and antimicrobial resistance (AMR), underscoring the importance of regional and robust pathogen genomics capacities. However, a significant disparity exists among EAC Partner States in harnessing bacterial pathogen sequencing and data analysis capabilities for effective AMR surveillance and outbreak response. This study assesses the current landscape and challenges associated with pathogen next-generation sequencing (NGS) within EAC, explicitly focusing on World Health Organization (WHO) AMR-priority pathogens. The assessment adopts a comprehensive approach, integrating a questionnaire-based survey amongst National Public Health Laboratories (NPHLs) with an analysis of publicly available metadata on bacterial pathogens isolated in the EAC countries. In addition to the heavy reliance on third-party organizations for bacterial NGS, the findings reveal a significant disparity among EAC member States in leveraging bacterial pathogen sequencing and data analysis. Approximately 97% (n = 4,462) of publicly available high-quality bacterial genome assemblies of samples collected in the EAC were processed and analyzed by external organizations, mainly in Europe and North America. Tanzania led in-country sequencing efforts, followed by Kenya and Uganda. The other EAC countries had no publicly available samples or had all their samples sequenced and analyzed outside the region. Insufficient local NGS sequencing facilities, limited bioinformatics expertise, lack of adequate computing resources, and inadequate data-sharing mechanisms are among the most pressing challenges that hinder the EAC's NPHLs from effectively leveraging pathogen genomics data. These insights emphasized the need to strengthen microbial pathogen sequencing and data analysis capabilities within the EAC to empower these laboratories to conduct pathogen sequencing and data analysis independently. Substantial investments in equipment, technology, and capacity-building initiatives are crucial for supporting regional preparedness against infectious disease outbreaks and mitigating the impact of AMR burden. In addition, collaborative efforts should be developed to narrow the gap, remedy regional imbalances, and harmonize NGS data standards. Supporting regional collaboration, strengthening in-country genomics capabilities, and investing in long-term training programs will ultimately improve pathogen data generation and foster a robust NGS-driven AMR surveillance and outbreak response in the EAC, thereby supporting global health initiatives.

Implications of Race Adjustment in Lung-Function Equations.

BACKGROUND: Adjustment for race is discouraged in lung-function testing, but the implications of adopting race-neutral equations have not been comprehensively quantified. METHODS: We obtained longitudinal data from 369,077 participants in the National Health and Nutrition Examination Survey, U.K. Biobank, the Multi-Ethnic Study of Atherosclerosis, and the Organ Procurement and Transplantation Network. Using these data, we compared the race-based 2012 Global Lung Function Initiative (GLI-2012) equations with race-neutral equations introduced in 2022 (GLI-Global). Evaluated outcomes included national projections of clinical, occupational, and financial reclassifications; individual lung-allocation scores for transplantation priority; and concordance statistics (C statistics) for clinical prediction tasks. RESULTS: Among the 249 million persons in the United States between 6 and 79 years of age who are able to produce high-quality spirometric results, the use of GLI-Global equations may reclassify ventilatory impairment for 12.5 million persons, medical impairment ratings for 8.16 million, occupational eligibility for 2.28 million, grading of chronic obstructive pulmonary disease for 2.05 million, and military disability compensation for 413,000. These potential changes differed according to race; for example, classifications of nonobstructive ventilatory impairment may change dramatically, increasing 141% (95% confidence interval [CI], 113 to 169) among Black persons and decreasing 69% (95% CI, 63 to 74) among White persons. Annual disability payments may increase by more than $1 billion among Black veterans and decrease by $0.5 billion among White veterans. GLI-2012 and GLI-Global equations had similar discriminative accuracy with regard to respiratory symptoms, health care utilization, new-onset disease, death from any cause, death related to respiratory disease, and death among persons on a transplant waiting list, with differences in C statistics ranging from -0.008 to 0.011. CONCLUSIONS: The use of race-based and race-neutral equations generated similarly accurate predictions of respiratory outcomes but assigned different disease classifications, occupational eligibility, and disability compensation for millions of persons, with effects diverging according to race. (Funded by the National Heart Lung and Blood Institute and the National Institute of Environmental Health Sciences.).

Assessment of the Impact of RNase in Patients With Severe Fatigue Related to Post-Acute Sequelae of SARS-CoV-2 Infection (PASC): A Randomized Phase 2 Trial of RSLV-132.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and RNA debris persist in viral reservoirs for weeks to months following infection, potentially triggering interferon production and chronic inflammation. RSLV-132 is a biologic drug composed of catalytically active human RNase1 fused to human IgG1 Fc and is designed to remain in circulation and digest extracellular RNA. We hypothesized that removal of SARS-CoV-2 viral RNA from latent reservoirs may improve inflammation, neuroinflammation, and fatigue associated with post-acute sequelae of SARS-CoV-2 infection (PASC). METHODS: This was a phase 2, double-blind, placebo-controlled randomized clinical trial in participants with a 24-week history of PASC and severe fatigue. The primary endpoint of the trial assessed the impact of 6 intravenous doses of RSLV-132 on the mean change from baseline at day 71 in the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a (PROMIS Fatigue SF 7a). RESULTS: A statistically significant difference on day 71 was not observed with respect to the primary or secondary endpoints. This was likely due to a placebo response that increased during the trial. Statistically significant improvement in fatigue as measured by the PROMIS Fatigue SF 7a, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Physicians Global Assessment (PGA) instruments were observed earlier in the trial, with women demonstrating greater responses to RSLV-132 than men. CONCLUSION: While fatigue was not statistically significantly improved at Day 71, earlier timepoints revealed statistically significant improvement in fatigue and physician global assessment. The data suggest eliminating latent viral RNA by increasing serum RNase activity may improve fatigue in PASC patients. Women may respond better to this approach than men. Future studies will aim to confirm these findings.

Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries.

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

Reducing Hospitalizations and Multidrug-Resistant Organisms via Regional Decolonization in Hospitals and Nursing Homes.

Importance: Infections due to multidrug-resistant organisms (MDROs) are associated with increased morbidity, mortality, length of hospitalization, and health care costs. Regional interventions may be advantageous in mitigating MDROs and associated infections. Objective: To evaluate whether implementation of a decolonization collaborative is associated with reduced regional MDRO prevalence, incident clinical cultures, infection-related hospitalizations, costs, and deaths. Design, Setting, and Participants: This quality improvement study was conducted from July 1, 2017, to July 31, 2019, across 35 health care facilities in Orange County, California. Exposures: Chlorhexidine bathing and nasal iodophor antisepsis for residents in long-term care and hospitalized patients in contact precautions (CP). Main Outcomes and Measures: Baseline and end of intervention MDRO point prevalence among participating facilities; incident MDRO (nonscreening) clinical cultures among participating and nonparticipating facilities; and infection-related hospitalizations and associated costs and deaths among residents in participating and nonparticipating nursing homes (NHs). Results: Thirty-five facilities (16 hospitals, 16 NHs, 3 long-term acute care hospitals [LTACHs]) adopted the intervention. Comparing decolonization with baseline periods among participating facilities, the mean (SD) MDRO prevalence decreased from 63.9% (12.2%) to 49.9% (11.3%) among NHs, from 80.0% (7.2%) to 53.3% (13.3%) among LTACHs (odds ratio [OR] for NHs and LTACHs, 0.48; 95% CI, 0.40-0.57), and from 64.1% (8.5%) to 55.4% (13.8%) (OR, 0.75; 95% CI, 0.60-0.93) among hospitalized patients in CP. When comparing decolonization with baseline among NHs, the mean (SD) monthly incident MDRO clinical cultures changed from 2.7 (1.9) to 1.7 (1.1) among participating NHs, from 1.7 (1.4) to 1.5 (1.1) among nonparticipating NHs (group × period interaction reduction, 30.4%; 95% CI, 16.4%-42.1%), from 25.5 (18.6) to 25.0 (15.9) among participating hospitals, from 12.5 (10.1) to 14.3 (10.2) among nonparticipating hospitals (group × period interaction reduction, 12.9%; 95% CI, 3.3%-21.5%), and from 14.8 (8.6) to 8.2 (6.1) among LTACHs (all facilities participating; 22.5% reduction; 95% CI, 4.4%-37.1%). For NHs, the rate of infection-related hospitalizations per 1000 resident-days changed from 2.31 during baseline to 1.94 during intervention among participating NHs, and from 1.90 to 2.03 among nonparticipating NHs (group × period interaction reduction, 26.7%; 95% CI, 19.0%-34.5%). Associated hospitalization costs per 1000 resident-days changed from $64 651 to $55 149 among participating NHs and from $55 151 to $59 327 among nonparticipating NHs (group × period interaction reduction, 26.8%; 95% CI, 26.7%-26.9%). Associated hospitalization deaths per 1000 resident-days changed from 0.29 to 0.25 among participating NHs and from 0.23 to 0.24 among nonparticipating NHs (group × period interaction reduction, 23.7%; 95% CI, 4.5%-43.0%). Conclusions and Relevance: A regional collaborative involving universal decolonization in long-term care facilities and targeted decolonization among hospital patients in CP was associated with lower MDRO carriage, infections, hospitalizations, costs, and deaths.

Do Medicaid Expenditures Increase After Adults Exit Permanent Supportive Housing?

The effects of homelessness and permanent supportive housing (PSH) on health care utilization have been well documented. Prior research on the association between PSH entry and Medicaid expenditures have indicated that such housing support could result in savings to Medicaid programs; however, whether changes occur in health care use and expenditures after individuals exit PSH is unknown. If efficiency gains from PSH persist after the individual leaves PSH, the savings to payers such as Medicaid may continue even after the costs to provide housing for a PSH recipient have ended. We used linked Medicaid and housing data from Pennsylvania to examine changes in the level and composition of Medicaid expenditures for 580 adult enrollees during the 12 months before and after exit from PSH adjusting for relevant covariates. In adjusted analyses, we estimated that monthly spending declined by $200.32 (95% CI: $323.50, $75.15) in the first quarter post-exit and by $267.63 (95% CI: $406.10, $127.10) in the third quarter. Our findings suggest that PSH may have sustained budgetary benefits to state Medicaid agencies even for beneficiaries exiting the program. However, more research is needed to understand if these reductions in expenditures last beyond 12 months and do not reflect under-use of care that may be important for managing health over the long-term.

The double burden of malnutrition in individuals: Identifying key challenges and re-thinking research focus.

The 'double burden of malnutrition' is a global health challenge that increasingly affects populations in both low- and middle-income countries (LMICs). This phenomenon refers to the coexistence of undernutrition and overweight or obesity, as well as other diet-related non-communicable diseases, in the same population, household or even individual. While noteworthy progress has been made in reducing undernutrition in some parts of the world, in many of these areas, the prevalence of overweight and obesity is increasing, particularly in urban areas, resulting in greater numbers of people who were undernourished in childhood and have overweight or obesity in adulthood. This creates a complex and challenging situation for research experts and policymakers who must simultaneously address the public health burdens of undernutrition and overweight/obesity. This review identifies key challenges and limitations in the current research on the double burden of malnutrition in individuals, including the need for a more comprehensive and nuanced understanding of the drivers of malnutrition, the importance of context-specific interventions and the need for greater attention to the food environment and food systems. We advocate for the re-evaluation of research strategies and focus, with a greater emphasis on multidisciplinary and systems approaches and greater attention to the synergistic relationship between the biological, environmental, commercial and socio-economic determinants of malnutrition. Addressing these key challenges can enable us to better comprehend and tackle the multifaceted and dynamic issues of the double burden of malnutrition, particularly in individuals and work towards more effective and sustainable solutions.

What are the impacts of alcohol supply reduction measures on police-recorded adult domestic and family violence in the Northern Territory of Australia?

BACKGROUND: During 2017-18, the Northern Territory (NT) introduced a Banned Drinker Register (BDR) and Minimum Unit Price (MUP) NT-wide; Police Auxiliary Liquor Inspectors (PALIs) in three regional towns; and restrictions on daily purchases/opening hours (DPOH) in one regional town. The BDR is an individual-level alcohol ban; MUP is a pricing policy; and PALIs enforce bans on restricted areas at takeaway outlets. This study examines the impact of these policies on adult domestic and family violence (DFV). METHODS: We examined DFV assaults and breaches of violence orders from January 2014 - February 2020 using interrupted time series models for NT, Greater Darwin, Katherine, Tennant Creek, and Alice Springs. To account for increasing numbers of individuals on the BDR we tested two timepoints (Sept 2017, March 2018). FINDINGS: Following DPOH, assaults (78 %) and alcohol-involved assaults (92 %) decreased in Tennant Creek. After PALIs, assaults (79 %) in Tennant Creek, and breaches (39 %) and alcohol-involved breaches (58 %) in Katherine decreased. After MUP, assaults (11 %), alcohol-involved assaults (21 %) and alcohol-involved breaches (21%) decreased NT wide. After MUP/PALIs in Alice Springs, alcohol-involved assaults (33 %), breaches (42 %), and alcohol-involved breaches (57 %) decreased. BDR (Sept 2017) found increases in assaults (44 %) and alcohol-involved assaults (39 %) in Katherine and assaults (10%) and alcohol-involved assaults NT-wide (17 %). There were increases of 21 %-45 % in breaches NT-wide, in Darwin, Katherine, and Alice Springs. Following March 2018 found increases in assaults (33 %) and alcohol-involved assaults (48 %) in Katherine. There were increases - from 20 % to 56 % - in breaches in NT-wide, Katherine, and Alice Springs. CONCLUSION: PALIs and DPOH were associated with some reductions in DFV; the BDR was associated with some increases. The upward trend commences prior to the BDR, so it is also plausible that the BDR had no effect on DFV outcomes. Although MUP was associated with reductions in the NT-wide model, there were no changes in sites without cooccurring PALIs.

Approaches to Engaging Men During Primary Healthcare Encounters: A scoping review.

Gender-responsive healthcare is critical to advancing men's health given that masculinities intersect with other social determinants to impact help-seeking, engagement with primary healthcare, and patient outcomes. A scoping review was undertaken with the aim to synthesize gender-responsive approaches used by healthcare providers (HCPs) to engage men with primary healthcare. MEDLINE, PubMed, CINAHL, and PsycINFO databases were searched for articles published between 2000 and February 2024. Titles and abstracts for 15,659 citations were reviewed, and 97 articles met the inclusion criteria. Data were extracted and analyzed thematically. Thirty-three approaches were synthesized from across counseling/psychology, general practice, social work, nursing, psychiatry, pharmacy, and unspecified primary healthcare settings. These were organized into three interrelated themes: (a) tailoring communication to reach men; (b) purposefully structuring treatment to meet men's health needs, and (c) centering the therapeutic alliance to retain men in care. Strength-based and asset-building approaches focused on reading and responding to a diversity of masculinities was reinforced across the three findings. While these approaches are recommended for the judicious integration into health practitioner education and practice, this review highlighted that the evidence remains underdeveloped, particularly for men who experience health inequities. Critical priorities for further research include intersectional considerations and operationalizing gender-responsive healthcare approaches for men and its outcomes, particularly at first point-of-contact encounters.

Cost-effectiveness of Accepting Kidneys From Deceased Donors With Common Cancers-A Modeling Study.

BACKGROUND: The disparity between the demand for and supply of kidney transplants has resulted in prolonged waiting times for patients with kidney failure. A potential approach to address this shortage is to consider kidneys from donors with a history of common cancers, such as breast, prostate, and colorectal cancers. METHODS: We used a patient-level Markov model to evaluate the outcomes of accepting kidneys from deceased donors with a perceived history of breast, prostate, or colorectal cancer characterized by minimal to intermediate transmission risk. Data from the Australian transplant registry were used in this analysis. The study compared the costs and quality-adjusted life years (QALYs) from the perspective of the Australian healthcare system between the proposed practice of accepting these donors and the conservative practice of declining them. The model simulated outcomes for 1500 individuals waitlisted for a deceased donor kidney transplant for a 25-y horizon. RESULTS: Under the proposed practice, when an additional 15 donors with minimal to intermediate cancer transmission risk were accepted, QALY gains ranged from 7.32 to 20.12. This translates to an approximate increase of 7 to 20 additional years of perfect health. The shift in practice also led to substantial cost savings, ranging between $1.06 and $2.3 million. CONCLUSIONS: The proposed practice of accepting kidneys from deceased donors with a history of common cancers with minimal to intermediate transmission risk offers a promising solution to bridge the gap between demand and supply. This approach likely results in QALY gains for recipients and significant cost savings for the health system.

A new ground level neutron monitor for space weather assessment.

We report on a new ground-level neutron monitor design for studying cosmic rays and fluxes of solar energetic particles at the Earth's surface. The first-of-its-kind instrument, named the NM-2023 after the year it was standardised and following convention, will be installed at a United Kingdom Meteorological Office observatory (expected completion mid 2024) and will reintroduce such monitoring in the UK for the first time since ca. 1984. Monte Carlo radiation transport code is used for the development and application of parameterised models to investigate alternative neutron detectors, their location and bulk material geometry in a realistic cosmic ray neutron field. Benchmarked against a model of the current and most widespread design standardised in 1964 (the NM-64), two main parameterisation studies are conducted; a simplified standard model and a concept slab parameterisation. We show that the NM-64 standard is well optimised for the intended large-diameter boron trifluoride (BF 3 ) proportional counters but not for multiple smaller diameter counters. The new design (based on a novel slab arrangement) produces comparable counting efficiencies to an NM-64 with six BF 3 counters and has the added advantage of being more compact, lower cost and avoids the use of highly toxic BF 3 .

Patient Resiliency and Caregiver Burden After Traumatic Spinal Cord Injury Resulting in Quadriplegia.

Traumatic spinal cord injury (tSCI) resulting in quadriplegia is a life-altering injury for patients and caregivers. We conducted a retrospective review of patients treated for tSCI and quadriplegia at a level 1 trauma center to assess quality of life (QOL), socioeconomic factors, and mortality. Patients and caregivers were surveyed. Of the 65 patients included, 33 contacts were made. Seventeen surveys were completed (12 caregivers and 5 patients). Six unreachable patients were confirmed alive via medical record. Mortality rate among these 39 accessible patients was 23% (n = 9). Medicaid and uninsured patients experienced longer hospital length of stay (P < .0001) and discharged to home or nursing facilities (P < .0001) more often than those with private insurance or Medicare. Patients reported overall "good" QOL (80%) while caregivers reported overall decreased QOL markers. Our results reflect the resilience among this patient population, but also highlight the impact of this life-altering injury on the caregiver.

Trajectories of resting energy expenditure and performance of predictive equations in children hospitalized with an acute illness and malnutrition: a longitudinal study.

There is scarce data on energy expenditure in ill children with different degrees of malnutrition. This study aimed to determine resting energy expenditure (REE) trajectories in hospitalized malnourished children during and after hospitalization. We followed a cohort of children in Bangladesh and Malawi (2-23 months) with: no wasting (NW); moderate wasting (MW), severe wasting (SW), or edematous malnutrition (EM). REE was measured by indirect calorimetry at admission, discharge, 14-and-45-days post-discharge. 125 children (NW, n = 23; MW, n = 29; SW, n = 51; EM, n = 22), median age 9 (IQR 6, 14) months, provided 401 REE measurements. At admission, the REE of children with NW and MW was 67 (95% CI [58, 75]) and 70 (95% CI [63, 76]) kcal/kg/day, respectively, while REE in children with SW was higher, 79 kcal/kg/day (95% CI [74, 84], p = 0.018), than NW. REE in these groups was stable over time. In children with EM, REE increased from admission to discharge (65 kcal/kg/day, 95% CI [56, 73]) to 79 (95% CI [72, 86], p = 0.0014) and was stable hereafter. Predictive equations underestimated REE in 92% of participants at all time points. Recommended feeding targets during the acute phase of illness in severely malnourished children exceeded REE. Acutely ill malnourished children are at risk of being overfed when implementing current international guidelines.

Primaquine in glucose-6-phosphate dehydrogenase deficiency: an adaptive pharmacometric assessment of ascending dose regimens in healthy volunteers.

Background: Primaquine is an 8-aminoquinoline antimalarial. It is the only widely available treatment to prevent relapses of Plasmodium vivax malaria. The 8-aminoquinolines cause dose-dependent haemolysis in glucose-6-phosphate dehydrogenase deficiency (G6PDd). G6PDd is common in malaria endemic areas but testing is often not available. As a consequence primaquine is underused. Methods: We conducted an adaptive pharmacometric study to characterise the relationship between primaquine dose and haemolysis in G6PDd. The aim was to explore shorter and safer primaquine radical cure regimens compared to the currently recommended 8-weekly regimen (0.75 mg/kg once weekly), potentially obviating the need for G6PD testing. Hemizygous G6PDd healthy adult Thai and Burmese male volunteers were admitted to the Hospital for Tropical Diseases in Bangkok. In Part 1, volunteers were given ascending dose primaquine regimens whereby daily doses were increased from 7.5 mg up to 45 mg over 15-20 days. In Part 2 conducted at least 6 months later, a single primaquine 45 mg dose was given. Results: 24 volunteers were enrolled in Part 1, and 16 in Part 2 (13 participated in both studies). In three volunteers, the ascending dose regimen was stopped because of haemolysis (n=1) and asymptomatic increases in transaminases (n=2; one was hepatitis E positive). Otherwise the ascending regimens were well tolerated with no drug-related serious adverse events. In Part 1, the median haemoglobin concentration decline was 3.7 g/dL (range: 2.1-5.9; relative decline of 26% [range: 15-40%]). Primaquine doses up to 0.87 mg/kg/day were tolerated subsequently without clinically significant further falls in haemoglobin. In Part 2, the median haemoglobin concentration decline was 1.7 g/dL (range 0.9-4.1; relative fall of 12% [range: 7-30% decrease]). The ascending dose primaquine regimens gave seven times more drug but resulted in only double the haemoglobin decline. Conclusions: In patients with Southeast Asian G6PDd variants, full radical cure treatment can be given in under 3 weeks compared with the current 8-week regimen. Funding: Medical Research Council of the United Kingdom (MR/R015252/1) and Wellcome (093956/Z/10/C, 223253/Z/21/Z). Clinical trial number: Thai Clinical Trial Registry: TCTR20170830002 and TCTR20220317004.

Assessment of Visual Function with Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa in the Randomized XIRIUS Phase 2/3 Study.

PURPOSE: Cotoretigene toliparvovec (BIIB112/AAV8-RPGR) is an investigational vector-based gene therapy designed to provide a full-length, codon-optimized retinitis pigmentosa GTPase regulator (RPGR) protein to individuals with RPGR-associated X-linked retinitis pigmentosa (XLRP). We assessed efficacy and tolerability of cotoretigene toliparvovec subretinal gene therapy. DESIGN: Part 2 of the XIRIUS trial (ClinicalTrials.gov identifier, NCT03116113) was a phase 2/3, 12-month, randomized (1:1:1) dose-expansion study. PARTICIPANTS: Male patients ≥10 years of age with RPGR-associated XLRP were included. METHODS: Participants were randomized 1:1:1 to receive low-dose subretinal cotoretigene toliparvovec (5 × 1010 vector genomes/eye), high-dose cotoretigene toliparvovec (2.5 × 1011 vector genomes/eye) or to be an untreated control participant. MAIN OUTCOME MEASURES: The primary end point was the percentage of participants meeting microperimetry responder criteria (≥ 7-dB improvement at ≥ 5 of 16 central loci). Secondary end points included change from baseline in retinal sensitivity at the central 16 loci and the entire 68 loci at 12 months and change from baseline in low-luminance visual acuity (LLVA) at 12 months, as well as the proportion of eyes with a ≥ 15-Early Treatment Diabetic Retinopathy Study ETDRS letter LLVA and ≥ 10-ETDRS letter LLVA change from baseline at month 12. RESULTS: Because of the impact of the COVID-19 pandemic, enrollment ended before reaching the initial target, leaving the trial underpowered. Twenty-nine participants were included (low-dose group, n = 10; high-dose group, n = 10; control group, n = 9). At month 12, the percentage of participants meeting microperimetry responder criteria was not significantly different between either cotoretigene toliparvovec group (low dose, 37.5% [P = 0.3181]; high dose, 25.0% [P = 0.5177]) and the control group (22.2%). However, the mean change from baseline in microperimetry sensitivity improved significantly with the low-dose group versus the control group at month 12 (P = 0.0350). Significant improvement in LLVA occurred in the low-dose group versus the control group at month 12 (33.3% difference [80% confidence interval, 14.7%-55.2%]; P = 0.0498). Three ocular-related serious adverse events (SAEs) occurred in the low-dose group versus 7 SAEs in the high-dose group. CONCLUSIONS: The primary microperimetry end point was not met. Significant improvements in LLVA and mean microperimetry were observed compared with controls and fewer SAEs occured with low-dose compared with high dose cotoretigene toliparvovec. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Patient-centric Comparability Assessment of Biopharmaceuticals.

The comparability assessment of a biological product after implementing a manufacturing process change should involve a risk-based approach. Process changes may occur at any stage of the product lifecycle: early development, clinical manufacture for pivotal trials, or post-approval. The risk of the change to impact product quality varies. The design of the comparability assessment should be adapted accordingly. A working group reviewed and consolidated industry approaches to assess comparability of traditional protein-based biological products during clinical development and post-approval. The insights compiled in this review article encompass topics such as a risk-evaluation strategy, the design of comparability studies, definition of assessment criteria for comparability, holistic evaluation of data, and the regulatory submission strategy. These practices can be leveraged across the industry to help companies in design and execution of comparability assessments, and to inform discussions with global regulators.